EP3154692B1 - Fluidic module, apparatus and method for handling a liquid - Google Patents

Description

The present invention relates to a fluidic module, apparatus and method for handling liquid which are particularly suitable for handling such as retaining and releasing or pumping liquid in a centrifugal microfluidic system.

Centrifugal microfluidics deals with the handling of liquids in the pl to ml range in rotating systems. Such systems are mostly disposable polymer cartridges used in or in place of centrifuge rotors, with the intention of enabling completely novel processes that can not be imaged by manual processes or pipetting robots due to the required precision or volume, or to automate laboratory processes. Standard laboratory processes such as pipetting, centrifuging, mixing or aliquoting can be implemented in a microfluidic cartridge. For this purpose, the cartridges contain channels for fluid guidance, as well as chambers for collecting liquids. The cartridges are subjected to a predefined sequence of rotational frequencies, the frequency protocol, so that the fluids in the cartridges can be guided by inertial forces into corresponding chambers. Centrifugal microfluidics is mainly used in laboratory analysis and mobile diagnostics.

The hitherto most common type of cartridges are centrifugal microfluidic disks known, for example, under the names "Lab-on-a-disk", "Lab-Disk", and "Lab-on-CD", which fall into special Processing devices are used. Other formats, such as a microfluidic centrifuge tube, known as "LabTube", can be used in rotors of existing standard laboratory equipment.

One essential basic operation that must be performed in centrifugal microfluidic cartridges is the selective retention and release of liquids. The problem is to liquids at defined rotational frequencies or defined To transfer changes in the rotational frequencies of a first fluid chamber in a second fluid chamber, or to retain liquids at defined rotational frequencies or defined changes in the rotational frequencies in a first chamber. For the use of this basic operation in a possible product, the robustness of the process is of paramount importance. Furthermore, the basic operation should be realized as a monolithic integrated valve, so that no additional components or materials - which substantially increase the cost of the cartridge by material costs or additional assembly and connection technology (assembly) - are required.

Monolithic integrated valves in centrifugal microfluidic systems are well known in the art. So is at R. Gorkin et al., "Pneumatic Pumping in Centrifugal Microfluidic Platform", Microfluid Nanofluid, 2010, 9, pp. 541-549 , a method for pumping peumatischen described, which makes it possible to retain liquid in a first phase at defined, high rotational frequencies (usually several 10 Hz) in a first fluid chamber to subsequently in a second phase at defined, lower rotational frequencies, the liquid in to direct a second fluid chamber. In this case, liquid is transferred with increasing rotational frequency from a reservoir into a first fluid chamber. With increased rotational frequency, the liquid is retained in the first fluid chamber, wherein a trapped in the first fluid chamber gas volume is compressed. With decreasing rotational frequency, the trapped gas volume expands again and displaces part of the liquid into a curved, acting as a siphon channel. When the siphon apex is exceeded, an additional centrifugal pressure is created which causes the liquid to be transferred from the first to the second fluid chamber. Thus, in the first phase, a volume of gas trapped by the process liquid in the first fluid chamber is compressed to use in the second phase the corresponding expansion of the gas volume for the return of the liquid.

In the pneumatic pumping process, in the first phase, a certain threshold of the rotational frequency (threshold frequency) must be exceeded in order to retain the fluid in the first fluid chamber. The same threshold frequency must subsequently be exceeded in order to return the liquid via the siphon vertex and to start the fluid transfer from the first fluid chamber into the second fluid chamber.

So that the filling of the siphon is independent of capillary forces, the threshold frequency should be as high as possible.

S. Zehnle, F. Schwemmer, G. Roth, F. von Stetten, R. Zengerle and N. Paust, "Centrifugodynamic Inward Pumping of Liquids on a Centrifugal Microfluidic Platform", Lab Chip, 2012, 12, pp. 5142-5145 describe a method for centrifugal-dynamic inward pumping, which makes it possible to retain liquid in a first phase at defined, high rotational frequencies (usually several 10 Hz) in a first fluid chamber, to subsequently in a second phase with rapidly decreasing rotational frequency a large part to direct the liquid into a second, radially inwardly located fluid chamber. In this case, liquid is transferred with increasing rotational frequency from a reservoir into a first fluid chamber. With increased rotational frequency, the liquid is retained in the first fluid chamber, wherein a trapped in the first fluid chamber gas volume is compressed. With rapidly decreasing rotational frequency, the trapped gas volume expands again and displaces most of the fluid through that channel, which has the lower flow resistance. Thus, in the first phase, a volume of gas trapped by the process liquid in the first chamber is compressed to utilize in the second phase the energy of the compressed gas for the radial inward pumping of the liquid. A corresponding method is in the DE 10 2012 202 775 A1 described.

As stated above, the threshold frequency in pneumatic pumping should be as high as possible in order to minimize the influence of capillary forces. This means that the siphon is usually filled even at high rotational frequencies (even if the deceleration rate is several 10 Hz / s). The inventors have realized that this entails disadvantages. When reaching the liquid of the siphon apex at higher rotational frequencies, it can lead to instability of the liquid / gas interface at the siphon apex. The inclusion of air bubbles and thus the malfunction of the siphon can be the result. This effect could be minimized in a siphon with a small cross-sectional area, but this would increase the dependence on capillary forces, as well as the fluidic resistance and thus the time required for the fluid transfer. When pumping liquid through a siphon at higher rotational frequencies, it can also lead to instability of the liquid / gas interface at the outer end of the siphon. Here too This can lead to the trapping of air bubbles and thus the functional failure of the siphons. Depending on the design of the siphon, the pressure in the siphon apex may become so low at high rotational frequency that the liquid evaporates and consequently gas bubble formation leads to the functional failure of the siphon. Even at lower rotational frequencies and thus lower negative pressure gas bubble formation may occur because due to the lower pressure in the apex region of the siphon, the solubility of gases, such as oxygen, reduced and thus outgas the insoluble amount of gas in the form of bubbles.

Will be an inward pumping, as for example in the DE 10 2012 202 775 A1 This is disadvantageous in that the entire amount of liquid is never transferred from the compression chamber to the catching chamber when used as a valve.

Another way to retain fluids is by taking advantage of the capillary force, which, controlled by the rotational frequency, must be overcome by the centrifugal force to move the fluid. However, such methods are highly dependent on the surface tension of the liquid and the surface condition of the fluidic channels and thus can not be classified as robust.

The object of the present invention is to provide a fluidic module, a device and a method for handling, in particular pumping, a liquid, which allow a time-controlled and decoupled from the centrifuge dynamics pumping over a certain radial distance.

This object is achieved by a fluidic module according to claim 1, an apparatus according to claim 10 and a method according to claim 12.

• einer ersten Kompressionskammer mit einem Fluideinlass und einem Fluidauslass;
• einer zweiten Kompressionskammer mit einem Fluideinlass;
• einem ersten Fluidkanal, der über den Fluideinlass der ersten Kompressionskammer mit der ersten Kompressionskammer verbunden ist; und
• einem zweiten Fluidkanal, der den Fluidauslass der ersten Kompressionskammer mit dem Fluideinlass der zweiten Kompressionskammer verbindet,
• wobei durch eine Drehung des Fluidikmoduls eine Flüssigkeit zentrifugal durch den ersten Fluidkanal in die erste Kompressionskammer und in den zweiten Fluidkanal treibbar ist, und dadurch ein kompressibles Medium in der zweiten Kompressionskammer einschließbar und komprimierbar ist,
• wobei durch Absenken der Drehfrequenz und dadurch bedingtes Ausdehnen des kompressiblen Mediums Flüssigkeit aus dem zweiten Fluidkanal in die erste Kompressionskammer, aus der ersten Kompressionskammer in einen Auslasskanal und durch den Auslasskanal treibbar ist,
• wobei zumindest eines der folgenden Merkmale erfüllt ist:
  • der zweite Fluidkanal weist einen höheren Strömungswiderstand auf als der Auslasskanal, und
  • der Fluideinlass der zweiten Kompressionskammer ist bezüglich des Rotationszentrums radial weiter außen angeordnet ist als der Fluidauslass der ersten Kompressionskammer.

Embodiments of the invention provide a fluidic module that is rotatable about a center of rotation, having the following features:

• a first compression chamber having a fluid inlet and a fluid outlet;
• a second compression chamber having a fluid inlet;
• a first fluid passage connected to the first compression chamber via the fluid inlet of the first compression chamber; and
• a second fluid passage connecting the fluid outlet of the first compression chamber with the fluid inlet of the second compression chamber,
• wherein a fluid is centrifugally drivable through the first fluid channel into the first compression chamber and into the second fluid channel by a rotation of the fluidic module, and thereby a compressible medium in the second compression chamber can be enclosed and compressed,
• whereby fluid can be driven out of the second fluid channel into the first compression chamber, out of the first compression chamber into an outlet channel and through the outlet channel by lowering the rotational frequency and thereby causing the compressible medium to expand;
• wherein at least one of the following features is fulfilled:
  • the second fluid channel has a higher flow resistance than the outlet channel, and
  • the fluid inlet of the second compression chamber is disposed radially farther outward with respect to the center of rotation than the fluid outlet of the first compression chamber.

Embodiments of the invention provide an apparatus for handling, in particular pumping, fluid with a fluidic module as described herein and a drive apparatus configured to apply rotations to the fluidic module at different rotational frequencies. The drive device is configured to, in a first phase, pressurize the fluidic module with rotation at a rotational frequency at or above a first rotational frequency at which fluid is centrifugally driven through the first fluid channel into the first compression chamber, at which first compression chamber is filled with the liquid and is driven at the liquid from the first compression chamber into the second fluid passage, thereby to enclose and compress the compressible medium in the second compression chamber. The drive device is further configured to lower the rotational frequency in a second phase after the first phase below a second rotational frequency at which the force exerted on the fluid by the compressed medium in the second compression chamber outweighs the centrifugal force exerted by the fluid, so that expands the compressible medium and thereby fluid is driven from the second fluid channel into the first compression chamber, from the first compression chamber into the outlet channel and through the outlet channel.

Embodiments of the invention provide a method of handling fluid with a fluidic module as described herein. In a first phase, the fluidic module is rotated with rotation at a rotational frequency at or above a first rotational frequency to centrifugally drive liquid through the first fluid channel into the first compression chamber to fill the first compression chamber with the fluid and to remove fluid from the first compression chamber driving the first compression chamber into the second fluid channel to thereby enclose and compress the compressible medium in the second compression chamber. In a second phase after the first phase, the rotational frequency is lowered below a second rotational frequency at which the force exerted on the fluid by the compressed medium in the second compression chamber outweighs the centrifugal force exerted by the fluid so that the compressible medium expands and thereby Fluid is driven from the second fluid channel into the first compression chamber, from the first compression chamber into the outlet channel and through the outlet channel.

Embodiments of the invention thus relate to fluidic modules, devices and methods suitable for controlled release and controlled passage of liquid through a channel, and more particularly to such fluidic modules, devices and methods suitable for timed pumping of a liquid in centrifuge rotors.

Embodiments of the invention are based on the realization that it is possible by providing a first compression chamber, a second compression chamber and a second fluid channel, which fluidly connects the first and the second compression chamber, and a corresponding design of the course and the dimensions of the second fluid channel. the dynamics of the pumping action through the exhaust passage during and after the reduction of the rotational frequency passive, that is to control without further change of the rotational frequency.

Thus, in embodiments of the invention, the second fluid channel may have a higher flow resistance than the outlet channel. For example, the cross section of the second fluid channel may be small enough to represent a flow resistance for the liquid that is higher than the flow resistance of the outlet channel. The viscosity of the liquid (e.g., water) may be significantly higher than the viscosity of the compressible medium (e.g., air). Thus, embodiments of the invention, due to the higher viscosity of the liquid, allow a delay in the pumping action through the outlet channel as long as the second fluid channel is filled with liquid. Only when the second fluid channel is partially or completely filled with the low-viscosity compressible medium, the pumping process takes place through the outlet channel at a much higher flow rate, which is not limited by the flow resistance in the second fluid channel. Due to the delay of the pumping process, the conduction of the liquid through the outlet channel thus at any rotational frequency, especially at standstill, take place.

In embodiments of the invention, the end of the second fluid channel may be located radially further out than the beginning of the second fluid channel, such that expansion of the compressible medium in the second compression chamber and the second fluid channel causes the centrifugal back pressure to be applied to the second fluid channel during emptying expansible compressible medium significantly decreases due to this course of the second fluid channel. In this case, this drop in the centrifugal counter-pressure is brought about by only a smaller change in the volume of the compressible medium, which means that the almost constant overpressure of the compressible medium is offset by a significant change in the centrifugal counter-pressure. This pressure change is compensated by the high pressure in the first compression chamber Flow rate is pumped into the outlet channel. Thus, embodiments of the invention provide high dynamics in draining the liquid from the first compression chamber. Due to the strong change in the centrifugal back pressure during emptying, but also during the filling of the second fluid channel not only the dynamics of the emptying of the first compression chamber, or the dynamics of the filling of the second compression chamber is affected, but also the rotational frequency, in which - the liquid levels are in equilibrium - the emptying of the first compression chamber takes place. Thus, embodiments of the invention allow adjustment of the switching frequencies due to the different radial positions of the fluid outlet of the first compression chamber and the fluid inlet of the second compression chamber.

In embodiments of the invention, the outlet channel may be at least partially formed by the first fluid channel. Thus, in embodiments of the invention, the first channel is the outlet channel. In alternative embodiments of the invention, the outlet channel includes a portion of the first fluid channel and a third fluid channel branching from the first fluid channel. In alternative embodiments, the outlet channel is a fluid channel separate from the first fluid channel, which opens at a radially outer portion or the radially outer end thereof into the first compression chamber. In embodiments, the outlet channel has a lower flow resistance than the first fluid channel. In embodiments, the outlet channel has a siphon, wherein an outlet end of the siphon with respect to the rotation center is arranged radially further out than the position at which the outlet channel opens into the first compression chamber.

Embodiments of the invention are centrifugal-pneumatic delay switches. In embodiments of the invention, there is first a delay of emptying a first compression chamber, whereupon dynamic emptying can take place without further change of the rotational frequency. These effects can be achieved either by the course of the second fluid channel (connection channel) in the centrifugal force field or by the higher flow resistance of the second fluid channel with respect to the outlet channel or by both.

Fig. 1A

bis 1D schematische Draufsichten auf Fluidikstrukturen eines Ausführungsbeispiels eines Fluidikmoduls, wobei ein Fluideinlass der zweiten Kompressionskammer radial weiter außen angeordnet ist als ein Fluidauslass der ersten Kompressionskammer;

Fig. 2

ein Diagramm zur Erläuterung von dem in den Fig. 1A bis 1D gezeigten Ausführungsbeispiel zugrundeliegenden Effekten;

Fig. 3

eine schematische Draufsicht auf Fluidikstrukturen gemäß einem Ausführungsbeispiel eines Fluidikmoduls, bei dem der zweite Fluidkanal einen größeren Fluidwiderstand aufweist als der Auslasskanal;

Fig. 4

eine schematische Draufsicht auf Fluidikstrukturen gemäß einem Ausführungsbeispiel eines Fluidikmoduls, bei dem der erste Kanal auch den Auslasskanal bildet;

Fig. 5

eine schematische Draufsicht auf Fluidikstrukturen gemäß einem Ausführungsbeispiel eines Fluidikmoduls, bei dem der Auslasskanal einen Siphon aufweist;

Fig. 6

und 7 schematische Seitenansicht zur Erläuterung von Ausführungsbeispielen von Vorrichtungen zum Handhaben von Flüssigkeit.

Embodiments of the invention are explained below with reference to the accompanying drawings. Show it:

Fig. 1A

1D are schematic plan views of fluidic structures of an embodiment of a fluidic module, wherein a fluid inlet of the second compression chamber is disposed radially further out than a fluid outlet of the first compression chamber;

Fig. 2

a diagram for explaining the in the Fig. 1A to 1D embodiment shown underlying effects;

Fig. 3

a schematic plan view of fluidic structures according to an embodiment of a fluidic module, wherein the second fluid channel has a greater fluid resistance than the outlet channel;

Fig. 4

a schematic plan view of fluidic structures according to an embodiment of a fluidic module, wherein the first channel also forms the outlet channel;

Fig. 5

a schematic plan view of fluidic structures according to an embodiment of a fluidic module, wherein the outlet channel has a siphon;

Fig. 6

and FIG. 7 shows a schematic side view for explaining exemplary embodiments of devices for handling liquid.

Before embodiments of the invention are explained in more detail, it should first be pointed out that examples of the invention can be found in particular in the field of centrifugal microfluidics, which involves the processing of liquids in the picoliter to milliliter range. Accordingly, the fluidic structures can have suitable dimensions in the micrometer range for handling corresponding volumes of liquid. In particular, embodiments of the invention can be applied to Centrifugal microfluidic systems find application, as they are known for example under the name "Lab-on-a-Disk".

As used herein, the term radial is meant to be radial with respect to the center of rotation about which the fluidic module or rotor is rotatable. Thus, in the centrifugal field, a radial direction is radially sloping away from the center of rotation and a radial direction toward the center of rotation is radially increasing. A fluid channel, the beginning of which is closer to the center of rotation than the end, is thus radially sloping, while a fluid channel, the beginning of which is farther from the center of rotation than its end, is radially increasing. A channel which has a radially rising section thus has directional components which rise radially or extend radially inwards. It is clear that such a channel does not have to run exactly along a radial line, but can run at an angle to the radial line or bent.

By compression chamber is meant herein a chamber that allows the compression of a compressible medium. In embodiments of the present invention, this may be a non-vented chamber. In embodiments, it may be a chamber, which indeed has a vent, the vent but for the compressible medium has such a high flow resistance, that still occurs by an inflowing liquid compressing the compressible medium and that by a by such a vent occurring pressure reduction in the compression chamber (in the relevant period) is negligible. As such, the first and second compression chambers described herein could also be considered as a compression chamber having two regions connected via the second fluid channel. In embodiments, the compression chambers, with the exception of the inlets and outlets described no further fluid openings. In alternative embodiments, the compression chamber may be coupled to additional compression volume via one or more optional additional channels. In yet alternative embodiments, one or more compression chambers may include a closable vent.

In general, in embodiments of the invention, different flow resistances (hydraulic resistances) of respective fluid channels can be achieved via different flow cross sections. In alternative embodiments, different flow resistances may also be achieved by other means, such as different channel lengths, obstacles integrated in the channels, and the like. As used herein, a fluid channel means a structure whose length dimension is greater from a fluid inlet to a fluid outlet, for example more than 5 times or more than 10 times greater than the dimension defining the flow area or define. Thus, a fluid channel has a flow resistance for flowing through it from the fluid inlet to the fluid outlet. In contrast, a fluid chamber is a chamber having dimensions such that a relevant flow resistance does not occur in the same.

Referring to the 6 and 7 First examples of centrifugal microfluidic systems are described, in which the invention can be used.

Fig. 6 shows a device with a fluidic module 10 in the form of a body of revolution, which has a substrate 12 and a lid 14. The substrate 12 and the cover 14 may be circular in plan view, with a central opening through which the rotary body 10 may be attached via a conventional fastening means 16 to a rotating part 18 of a drive device 20. The rotating part 18 is rotatably supported on a stationary part 22 of the drive device 20. The drive device 20 may be, for example, a conventional adjustable-speed centrifuge or a CD or DVD drive. A control device 24 may be provided, which is designed to control the drive device 20 in order to act on the rotation body 10 with rotations with different rotational frequencies. As will be appreciated by those skilled in the art, controller 24 may be implemented by, for example, a suitably programmed computing device or custom integrated circuit. The controller 24 may further be configured to control the drive device 20 upon manual inputs by a user to effect the required rotations of the rotating body. In either case, the controller 24 may be configured to control the drive device 20 to apply the required rotational frequencies to the rotating body Embodiments of the invention as described herein are to be implemented. As drive device 20, a conventional centrifuge with only one direction of rotation can be used.

The rotary body 10 has the required fluidic structures. The required fluidic structures may be formed by cavities and channels in the lid 14, the substrate 12 or in the substrate 12 and the lid 14. For example, in embodiments, fluidic structures may be imaged in the substrate 12 while fill openings and vents are formed in the lid 14. In embodiments, the patterned substrate (including fill openings and vents) is located at the top and the lid is located at the bottom.

For an alternative in Fig. 7 shown embodiment, fluidic modules 32 are inserted into a rotor 30 and form together with the rotor 30, the rotary body 10. The fluidic modules 32 may each have a substrate and a lid, in which corresponding fluidic structures may be formed again. The rotational body 10 formed by the rotor 30 and the fluidic modules 32 in turn can be acted upon by a drive device 20, which is controlled by the control device 24, with a rotation.

In the FIGS. 6 and 7 is a rotation center about which the fluidic module or the rotation body is rotatable, denoted by R.

In embodiments of the invention, the fluidic module or body having the fluidic structures may be formed of any suitable material, for example a plastic such as PMMA (polymethyl methacrylate), PC (polycarbonate), PVC (polyvinylchloride) or PDMS (Polydimethylsiloxane), glass or the like. The rotary body 10 may be considered as a centrifugal microfluidic platform.

In the following, reference will be made to FIGS Fig. 1A to 1D an embodiment of a fluidic module described with corresponding fluidic structures, wherein in the Fig. 1A to 1D the fluidic structures formed in a respective fluidic module are shown during different phases of operation.

The fluidic structures have a first fluid channel 2, which constitutes an inlet channel, a first compression chamber 3 and a second compression chamber 5, which are connected to one another via a second fluid channel 4, and a third fluid channel 1, which forms part of an outlet channel. More precisely, branches in the in the Fig. 1A to 1D As shown, the third fluid channel 1 at a branch 50 from the first fluid channel 2, so that a part of the first fluid channel between the first compression chamber 3 and the branch 50 and the third fluid channel represent the outlet channel. The third fluid channel 1 can have a lower flow resistance (that is, for example, a larger flow cross section) than the first fluid channel 2, so that a discharge of the first compression chamber 3 takes place to a greater extent through the third fluid channel 1.

A fluid inlet 6 of the first compression chamber 3, which is arranged in the exemplary embodiment at a radially outer end of the first compression chamber 3, is fluidically connected to the first fluid channel 2 and thus also to the third fluid channel 1. A fluid outlet 7 of the first compression chamber 3, which is arranged in the exemplary embodiment at a radially inner end of the first compression chamber 3, is fluidically connected to the second fluid channel 4.

A fluid inlet 8 of the second compression chamber 5, which is arranged in the exemplary embodiment at a radially outer end of the second compression chamber 5, is fluidically connected to the second fluid channel 4. The fluid inlet 8 of the second compression chamber 5 is located radially further outward than the fluid outlet 7 of the first compression chamber 3. Thus, a portion of the second fluid channel extends between the radially innermost portion 4a and the radially outermost portion 4b of the second fluid channel with respect to the center of rotation in Fig. 1A is denoted by R, radially outward.

Hereinafter, referring to the Fig. 1A to 1D and the diagram in Fig. 2 the operation of the embodiment of Fig. 1A to 1D explained in detail.

Phase 1: filling process

In operation, in a first phase, first at high rotational frequency, the first compression chamber 3 and the third channel (fluid outlet channel) 1 are partially filled via the first channel (fluid inlet channel) 2. For example, a radially inner end of the first fluid inlet channel may be fluidly coupled to an inlet chamber (not shown) for this purpose. In this case, in the first and in the second compression chamber 3, 5 and in the second fluid channel (fluid connection channel) 4, a compressible medium is enclosed, which is compressed by the fluid flowing into the first compression chamber, Fig. 1A , In this case, an overpressure builds up in the compressible medium, which is compensated by the centrifugal pressure of the liquid in the fluid inlet channel 2 and in the fluid outlet channel 1. If a rotational frequency f _{1 is} exceeded, the first compression chamber 3 is completely filled, and the liquid flows via the connecting channel 4 into the second compression chamber 5. After a sufficiently long time of filling, the system reaches the equilibrium state in which the liquid levels at a given rotational frequency do not change anymore. With decreasing rotational frequency, the enclosed compressed compressible medium (gas volume) expands again and liquid is pumped back through the first fluid channel 2 and the third fluid channel 1.

Phase 2a: Discharge process with dynamics due to hysteresis behavior

In the case that the fluid inlet 8 of the second compression chamber 5 is located radially further outward than the fluid outlet 7 of the first compression chamber 3, as in the case of FIGS Fig. 1A to 1D , The system is on reaching the rotational frequency f ₁ out of balance of centrifugal pressure and pneumatic (in the case of gas as a compressible medium) back pressure of the compressible medium. This imbalance will, as in Fig. 2 is shown compensated by fast ('dynamic') filling of the second compression chamber 5 until the equilibrium state is reached again. Fig. 1B shows the state at a rotation above the rotational frequency f ₁ .

If the rotational frequency is subsequently reduced again, the second compression chamber 5 is completely emptied only when the rotational frequency f _{2 is reached} , where f ₂ <f ₁ . As soon as f ₂ is exceeded, the connecting channel 4 is also emptied, as a result of which the System again is located outside the equilibrium of centrifugal pressure and pneumatic (in the case of gas as a compressible medium) back pressure of the compressible medium. This imbalance is according to Fig. 2 balanced by fast ('dynamic') emptying of the first compression chamber 3 until the equilibrium state is reached again.

This dynamic discharge caused by the pneumatic pressure produces high flow rates in the first fluid channel 2 and in the third fluid channel 1. Thus, the fluid in the third fluid channel 1 can reach radially inner positions that are not attainable in the equilibrium state. In other words, when emptying, the second fluid channel 3 increases the dynamics of the emptying process, whereby in the first and third fluid channels 2 and 1 higher filling levels are achieved than in the equilibrium state. In embodiments, the third fluid channel may be configured as a siphon, the outlet end of which is arranged radially further outward than the fluid inlet of the first compression chamber 3 in order to allow the entire liquid to drain off.

How out Fig. 2 can be seen, the liquid volumes in the fluid chambers 3 and 5 are subject to a hysteresis behavior with respect to the rotational frequency. In the event that the fluid inlet 8 of the fluid chamber is located radially farther outward than the fluid outlet 7 of the fluid chamber 3, the rotational frequency which increases in FIG Fig. 2 is marked by + arrows, a dynamic "sudden" filling of the fluid chamber 5 as soon as the rotational frequency f _{1 is} exceeded. With decreasing rotation frequency, the in Fig. 2 is marked by arrows with -, there is a dynamic "sudden" emptying of the fluid chamber 3 as soon as the rotational frequency f ₂ is exceeded.

Phase 2b: Discharge process with dynamics due to high flow resistance

Fig. 3 shows an alternative embodiment of the invention, in which the fluid inlet 8 of the second compression chamber 5 is not disposed radially further out than the fluid outlet of the first compression chamber. Rather, the in Fig. 3 1, the fluid inlet 8 of the second compression chamber 5 is radially further inward than the fluid outlet 7 of the first compression chamber 3. It should be noted that the rotational center in the figures is above the fluidic structure, as in FIG Fig. 3 in turn indicated by that designated by the reference numeral R rotation center.

In the event that the fluid inlet of the second compression chamber 5 is not radially further outward than the fluid outlet of the first compression chamber 3 (see. Fig. 3 ), the hysteresis behavior described in phase 2a does not occur: f ₂ ≥ f ₁ . A rapid, 'sudden' emptying of the compression chamber 3 is still achieved when the second fluid channel (connecting channel) 4 is a sufficiently high flow resistance for the liquid. In this case, when filling the compression chamber 5, the filling process is initially delayed by the high flow resistance in the connecting channel 4. After a sufficiently long time of filling, the system reaches the equilibrium state in which the liquid levels no longer change at a given rotational frequency.

If the rotational frequency is subsequently reduced, the return flow of the fluid is limited by the high flow resistance in the second fluid channel 4. With a sufficiently high flow resistance in the second fluid channel 4, the flow rate of the liquid during the backflow is so low even when the centrifuge rotor is at a standstill that the liquid fill levels in the fluid channels 1 and 2 change only slightly. During this Rückströmvorgang arbitrary rotational frequencies can be driven. In particular, the rotational frequency can be significantly below the critical value f ₁ or even zero. If the rotational frequency f ₁ falls short enough, then first the second compression chamber 5 is emptied, followed by the second fluid channel 4. While the second fluid channel 4 empties, the flow resistance in the second fluid channel 4 decreases (due to the lower viscosity of the compressible medium), so that the flow rate of the liquid increases during the backflow. With appropriate design of the geometry of the fluid channels and the compression chambers and at corresponding applied rotational frequencies, the flow rate during and after the emptying of the second fluid channel 4 may increase strong enough to reach in the third fluid channel (Fluidauslasskanal) 1, a radially inner position in the equilibrium state is unreachable.

In embodiments, the high flow resistance and the hysteresis behavior can be combined. The dynamics of the evacuation process can be increased or maximized be designed by both a connecting channel with a higher flow resistance than the outlet channel and the fluid inlet of the second compression chamber is arranged radially further outward than the fluid outlet of the first compression chamber. Thereby, a combination of the effects described above can be achieved, whereby it is possible to radially pump fluid in the outlet fluid channel even further inward.

Fig. 4 shows a further embodiment of the invention, in which the fluid inlet channel 2 also represents the fluid outlet channel. The effects described above can also be achieved in an analogous manner if the fluid inlet channel 2 is also operated as a fluid outlet channel.

Fig. 5 shows a further embodiment in which the fluid outlet channel 1 is designed as a siphon 60, so that at least one area, for example an outlet end 62 of the fluid outlet channel 1 radially outward than the fluid inlet 6 of the first compression chamber. This makes it possible to empty all the fluid from the fluidic structure having the described fluid channels and compression chambers.

In further embodiments, the second compression chamber may be divided into a plurality of compression chambers, which are connected in series via respective fluid channels. It is thus possible that the second compression chamber is again subdivided into a plurality of chambers. This makes it possible that certain chambers are filled exclusively with the compressible medium, while other chambers are filled with both the compressible medium and with the liquid.

In embodiments of the invention, a plurality of fluids supplied sequentially via the first fluid conduit may be used for the described operation, wherein one or more of the fluids may also be compressible.

In further embodiments, several of the described fluidic structures may be connected in parallel. By means of different channel geometries of the respective second fluid channels (connecting channels), a sequential switching of the fluids can then be predefined Times are reached. This is useful for automating a wide variety of bio-chemical processes.

In embodiments, the outlet channel need not open into the first compression chamber together with the inlet channel. The outlet channel can also open separately in a radially outer portion, for example, the radially outer end, in the first compression chamber, as long as the design ensures that the compressible medium can be compressed in the compression chamber. For example, the separate outlet channel can be designed to be closed by the liquid during the filling of the first compression chamber through the first fluid channel.

Exemplary typical values and geometries will now be given, it being understood, however, that the present invention is not limited to such values and geometries.

In a typical embodiment, the connection channel 4 may have a diameter of 20 μm to 200 μm. The volume of the compression chamber 3 may be between 25 and 75 .mu.l, for example, 50 .mu.l, and the volume of the compression chamber 4 may be at 150 ul to 360 ul. In embodiments of the invention, the volume of the first compression chamber is smaller, for example by a factor of 2 to 6, than the volume of the second compression chamber. Typical fluid volumes of the processed liquid can be 100 .mu.l, with volumes of 100 nl to 5 ml are conceivable with appropriate design of the chambers.

In embodiments of the invention, the outlet channel (including fluid inlet 6) may have a fluidic resistance (flow resistance) that is at least a factor of 2 or at least a factor of 10 smaller than the fluidic resistance of the connection channel. As has been described, this is not required in every embodiment. The viscosity of the processed liquid (eg water) may have a viscosity of from 30 to 90 higher than the compressible medium. For example, water as the liquid to be processed has an approximately 60 times higher viscosity than air as a compressible medium.

The fluidic structures need not have the shapes shown. For example, the chambers need not be rectangular, but may take any shape and may typically have rounded corners.

In embodiments of the invention, the maximum volume of the connection channel may be limited to about 0.3 μl to 0.5 μl. The minimum volume of the first compression chamber should be approximately 5 μl in this case. In principle, the connecting channel can also be designed with a large length, in which case also higher channel volumes would be conceivable. However, this would be associated with technical disadvantages, for example, a higher dead volume and a greater manufacturing effort.

In embodiments of the invention, a dynamic filling and emptying of a compression chamber takes place. Such dynamic filling and emptying can be achieved by the first and second compression chambers connected via the connecting channel. By this construction, filling and emptying can be achieved, which differs from dynamic filling and emptying in compression chambers, as known in the art.

In a compression chamber, as known in the art, the equilibrium level as a function of the rotational frequency is steady, i. with a very small change in the frequency of rotation (e.g., 0.1 Hz), there is always a very small change in the level of the compression chamber (e.g., <1%). The equilibrium level is defined as the level that sets at an infinitely long lasting constant rotation frequency.

In embodiments of the invention, a dynamic filling or a dynamic emptying with a hysteresis behavior can be achieved. For a certain rotational frequency range, due to the geometric arrangement of a chamber system (consisting of at least two compression chambers or pneumatic chambers) no rotational frequency in the equilibrium state, ie at infinite length of centrifugation, a defined liquid level can be assigned. Depending on whether a chamber system is being filled or emptied, a first or a second equilibrium level can be set. If this rotation frequency range is left, a new equilibrium level can be reached be sought, which deviates greatly from the current level. This large deviation can be compensated by accelerating the filling or emptying process, driven by centrifugal force or pneumatic force. In this type of dynamic filling or emptying of the equilibrium level is discontinuous as a function of the rotational frequency, ie that a very small change in the rotational frequency (eg 0.1 Hz) can lead to a large change in the level (eg> 20%) of the compression chamber.

In embodiments of the invention, a dynamic filling or a dynamic emptying can be achieved by using high flow resistance. The time course of the filling or emptying process can be significantly determined by channel cross sections. Thus, flow rates not equal to zero can be achieved due to viscous forces even at a constant rotational frequency. In particular, the replacement of different media in narrow channels and the associated changes in viscosity can lead to high flow rate changes, which can accelerate the filling and emptying even at a constant rotational frequency.

Embodiments of the present invention provide a fluidic module rotatable about a center of rotation, comprising: a first fluid channel; a first compression chamber fluidly coupled to the first fluid channel; a second compression chamber fluidly coupled to the first compression chamber via a second fluid channel; and a third fluid channel fluidly coupled to the first compression chamber. A liquid is centrifugally drivable through the first fluid channel into the first compression chamber. Upon rotation of the fluidic module, a compressible medium in the second compression chamber is trappable and compressible by a liquid forced by the centrifugal force through the first fluid channel into the first compression chamber, the second fluid channel, and the second compression chamber. Liquid is drivable by lowering the rotational frequency and thereby conditionally expanding the compressible medium from the second compression chamber and from the second fluid channel through the third fluid channel.

Embodiments of the invention provide a centrifugal microfluidic structure having a compression chamber divided into a first part and a second part by a fluid channel, wherein both parts can be reversibly at least partially filled with liquid and emptied. In operation, embodiments of the present invention include the generation of high dynamic fluidic switching operations that do not require rapid changes in rotational frequency. Furthermore, embodiments of the present invention have in operation the generation of highly dynamic fluidic switching operations, in which neither rapid changes of the rotational frequency, nor high fluidic resistances are required. Furthermore, embodiments of the invention show the maintenance of the compression of a compressible medium in a centrifuge rotor over a certain minimum period of time with any variation of the rotational frequency.

Embodiments of the present invention allow liquids to be held in fluid chambers while any rotational frequency protocol can be used for a certain time. This allows parallel processes to be carried out while maintaining the liquid and thus automating more complex processes than are known in the prior art.

Further, embodiments of the present invention also enable liquids to be maintained above a defined rotational frequency that may be well below the rotational frequency used to activate compliance with the fluid.

Embodiments of the present invention enable a highly dynamic release of fluid from fluid chambers even if only very low acceleration rates are available. This is especially useful for operation in standard laboratory centrifuges. Furthermore, they enable fluid transfer via a fluid outlet channel, in particular via a siphon, at low rotational frequencies. Thus, the aforementioned disadvantages of emptying can be avoided at high rotational frequencies.

Claims (14)

1. Fluidic module (10, 32) which may be rotated about a center of rotation (R), comprising:

   a first chamber (3) having a fluid inlet (6) and a fluid outlet (7);

   a second compression chamber (5) having a fluid inlet (8);

   a first fluid channel (2) connected to the first chamber (3) via the fluid inlet (6) of the first chamber (3); and

   a second fluid channel (4) connecting the fluid outlet (7) of the first chamber (3) to the fluid inlet (8) of the second compression chamber (5),

   wherein due to rotation of the fluidic module (10, 32) a liquid may be centrifugally driven into the first chamber (3), into the second fluid channel (4) and into the second compression chamber (5) through the first fluid channel (2), and thereby a compressible medium may be entrapped and compressed within the second compression chamber (5),

   wherein at least one of the following features is met:

   the second fluid channel (4) has a flow resistance for the liquid that is larger than that of the outlet channel (1, 2), and

   the fluid inlet (8) of the second compression chamber (5) is arranged, in relation to the center of rotation (R), radially further outward than is the fluid outlet (7) of the first chamber (3),

   characterized in that

   the first chamber (3) is a first compression chamber (3), and

   wherein, by lowering the rotary frequency and due to the resultant expansion of the compressible medium, liquid may be driven out of the second compression chamber (5) and of the second fluid channel (4) into the first compression chamber (3), out of the first compression chamber (3) into an outlet channel (1, 2) and through said outlet channel (1, 2),
2. Fluidic module (10, 32) as claimed in claim 1, wherein the first fluid channel (2) is the outlet channel (2).
3. Fluidic module (10, 32) as claimed in claim 1, wherein the outlet channel (1, 2) comprises part of the first fluid channel (2) and at least a third fluid channel (1) branching off from the first fluid channel (2).
4. Fluidic module (10, 32) as claimed in claim 3, wherein the at least one third fluid channel (1) has a flow resistance for the liquid that is lower than that of the first fluid channel (2).
5. Fluidic module (10, 32) as claimed in claims 1 to 4, wherein the outlet channel (1, 2) comprises a siphon (60), an outlet end (60) of the siphon (60) being arranged radially further outward, in relation to the center of rotation (R), than is the position where the outlet channel (1, 2) leads into the first compression chamber (3).
6. Fluidic module (10, 32) as claimed in claim 1, wherein the outlet channel is a fluid channel which is separate from the first fluid channel (2) and which leads into the first compression chamber (3) at a radially outer portion or at the radially outer end thereof.
7. Fluidic module (10, 32) as claimed in any of claims 1 to 6, wherein the fluid outlet (7) of the first compression chamber (3) is arranged at a portion or end, of the first compression chamber (3), that is arranged radially inward in relation to the center of rotation (R).
8. Fluidic module (10, 32) as claimed in any of claims 1 to 7, wherein the fluid inlet (8) of the second compression chamber (5) is arranged at a portion or end, of the second compression chamber (5), that is arranged radially outward in relation to the center of rotation (R).
9. Fluidic module (10, 32) as claimed in any of claims 1 to 8, wherein the second fluid channel (4) comprises, in the direction of flow from the second compression chamber (5) to the first compression chamber (4), in relation to the center of rotation (R), a portion, the beginning of which is further apart from the center of rotation (R) than is its end.
10. Device for handling liquid, comprising:

    a fluidic module (10, 32) as claimed in any of claims 1 to 9; and

    a drive device (20) configured to subject the fluidic module (10, 32) to rotations at different rotary frequencies,

    the drive device (20) being configured to subject the fluidic module (10, 32), during a first phase, to a rotation at a rotary frequency at or above a first rotary frequency at which liquid is centrifugally driven through the first fluid channel (2) into the first compression chamber (3), at which the first compression chamber (3) is filled with the liquid and at which liquid is driven out of the first compression chamber (3) into the second fluid channel (4) and into the second compression chamber (5) so as to thereby entrap and compress the compressible medium within the second compression chamber (5),

    the drive device (20) being configured to lower, during a second phase following the first phase, the rotary frequency to a value smaller than that of a second rotary frequency at which the force exerted on the liquid by the compressed medium within the second compression chamber (5) outweighs the centrifugal force exerted by the liquid, so that the compressible medium expands and so that consequently, liquid is driven out of the second compression chamber (5) and the second fluid channel (4) into the first compression chamber (3), out of the first compression chamber (3) into the outlet channel (1, 2) and through said outlet channel (1, 2).
11. Device as claimed in claim 10, wherein the fluid inlet (8) of the second compression chamber (5) is located, in relation to the center of rotation (R), radially further outward than is the fluid outlet (7) of the first compression chamber (3), the second rotary frequency being lower than the first rotary frequency, and wherein the drive device is configured to subject the fluidic module (10, 32), during an intermediate phase between the first phase and the second phase, to a rotary frequency ranging between the first rotary frequency and the second rotary frequency, without liquid being driven out of the second fluid channel (4) into the first compression chamber (3).
12. Method of handling liquid, comprising a fluidic module (10, 32) as claimed in any of claims 1 to 9, comprising:

    during a first phase, rotating the fluidic module (10, 32) with a rotation at a rotary frequency at or above a first rotary frequency so as to centrifugally drive liquid through the first fluid channel (2) into the first compression chamber (3) and into the second compression chamber (5) so as to fill the first compression chamber (3) with the liquid, and to drive liquid from the first compression chamber (3) into the second fluid channel (4) so as to thereby entrap and compress the compressible medium within the second compression chamber (5),

    during a second phase following the first phase, lowering the rotary frequency to a value smaller than that of a second rotary frequency at which the force exerted on the liquid by the compressed medium within the second compression chamber (5) outweighs the centrifugal force exerted by the liquid, so that the compressible medium expands and so that consequently, liquid is driven out of the second compression chamber (5) and the second fluid channel (4) into the first compression chamber (3), out of the first compression chamber (3) into the outlet channel (1, 2) and through said outlet channel (1, 2).
13. Method as claimed in claim 12, wherein the fluid inlet (8) of the second compression chamber (5) is located, in relation to the center of rotation (R), radially further outward than is the fluid outlet (7) of the first compression chamber (3), the second rotary frequency being lower than the first rotary frequency, and which method comprises rotating, during an intermediate phase between the first phase and the second phase, of the fluidic module at a rotary frequency ranging between the first rotary frequency and the second rotary frequency, without liquid being driven out of the second fluid channel (4) into the first compression chamber (3).
14. Method as claimed in claim 12 or 13, which comprises using a fluidic module, the fluid inlet (8) of which is arranged, in relation to the center of rotation (R), radially further outward than is the fluid outlet (7) of the first compression chamber (3), wherein during the first phase, when the rotary frequency increases, dynamic filling of the second compression chamber (5) starts as soon as a first rotary frequency f₁ is exceeded, and wherein during the second phase, when the rotary frequency decreases, dynamic emptying of the first compression chamber (3) starts as soon as a second rotary frequency f₂ is fallen below, wherein f₂ < f₁.

Images